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Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis

Author

Listed:
  • Gloria Ursino

    (University of Geneva
    University of Geneva)

  • Giorgio Ramadori

    (University of Geneva
    University of Geneva)

  • Anna Höfler

    (University of Geneva)

  • Soline Odouard

    (University of Geneva
    University of Geneva)

  • Pryscila D. S. Teixeira

    (University of Geneva
    University of Geneva)

  • Florian Visentin

    (University of Geneva
    University of Geneva)

  • Christelle Veyrat-Durebex

    (University of Geneva
    University of Geneva)

  • Giulia Lucibello

    (University of Geneva
    University of Geneva)

  • Raquel Firnkes

    (University of Geneva
    University of Geneva)

  • Serena Ricci

    (University of Geneva
    University of Geneva)

  • Claudia R. Vianna

    (University of Texas Southwestern Medical Center at Dallas)

  • Lin Jia

    (University of Texas Southwestern Medical Center at Dallas)

  • Mirjam Dirlewanger

    (University Hospitals of Geneva)

  • Philippe Klee

    (University Hospitals of Geneva)

  • Joel K. Elmquist

    (University of Texas Southwestern Medical Center at Dallas
    University of Texas Southwestern Medical Center at Dallas)

  • Johannes Roth

    (University of Munster
    University of Munster)

  • Thomas Vogl

    (University of Munster
    University of Munster)

  • Valérie M. Schwitzgebel

    (University of Geneva
    University of Geneva
    University Hospitals of Geneva)

  • François R. Jornayvaz

    (University of Geneva
    Geneva University Hospitals)

  • Andreas Boland

    (University of Geneva)

  • Roberto Coppari

    (University of Geneva
    University of Geneva)

Abstract

Unrestrained ketogenesis leads to life-threatening ketoacidosis whose incidence is high in patients with diabetes. While insulin therapy reduces ketogenesis this approach is sub-optimal. Here, we report an insulin-independent pathway able to normalize diabetic ketogenesis. By generating insulin deficient male mice lacking or re-expressing Toll-Like Receptor 4 (TLR4) only in liver or hepatocytes, we demonstrate that hepatic TLR4 in non-parenchymal cells mediates the ketogenesis-suppressing action of S100A9. Mechanistically, S100A9 acts extracellularly to activate the mechanistic target of rapamycin complex 1 (mTORC1) in a TLR4-dependent manner. Accordingly, hepatic-restricted but not hepatocyte-restricted loss of Tuberous Sclerosis Complex 1 (TSC1, an mTORC1 inhibitor) corrects insulin-deficiency-induced hyperketonemia. Therapeutically, recombinant S100A9 administration restrains ketogenesis and improves hyperglycemia without causing hypoglycemia in diabetic mice. Also, circulating S100A9 in patients with ketoacidosis is only marginally increased hence unveiling a window of opportunity to pharmacologically augment S100A9 for preventing unrestrained ketogenesis. In summary, our findings reveal the hepatic S100A9-TLR4-mTORC1 axis in non-parenchymal cells as a promising therapeutic target for restraining diabetic ketogenesis.

Suggested Citation

  • Gloria Ursino & Giorgio Ramadori & Anna Höfler & Soline Odouard & Pryscila D. S. Teixeira & Florian Visentin & Christelle Veyrat-Durebex & Giulia Lucibello & Raquel Firnkes & Serena Ricci & Claudia R., 2022. "Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31803-5
    DOI: 10.1038/s41467-022-31803-5
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